Researchers have developed a high-resolution map of gene regulatory interactions in human type 3 innate lymphoid cells (ILC3s), identifying candidate genes that may explain how noncoding genetic variants contribute to Crohn's disease and other immune-mediated disorders. The findings provide a resource for interpreting genome-wide association study (GWAS) signals and may improve understanding of the biological mechanisms underlying immune disease risk.
ILC3s are tissue-resident immune cells that help maintain the integrity of barrier tissues, particularly in the gastrointestinal tract, by producing cytokines such as interleukin (IL)-17 and IL-22. Although GWAS have identified hundreds of genetic variants associated with Crohn's disease, most occur outside protein-coding regions, making it difficult to determine which genes they affect.
To investigate this, the researchers generated high-resolution promoter capture Hi-C maps from primary human ILC3s isolated from tonsils and compared them with maps from CD4-positive T cells. They combined these data with epigenomic information and GWAS results, using newly developed analytical tools to link disease-associated variants with their likely target genes.
The analysis identified thousands of promoter-enhancer interactions and revealed substantial differences in gene regulatory networks between ILC3s and CD4-positive T cells. These cell-specific regulatory maps enabled the researchers to prioritize genes that may mediate genetic risk for immune disease.
For Crohn's disease, the researchers prioritized 109 candidate genes in ILC3s and 118 in CD4-positive T cells. The list included established immune-related genes such as IL10, IL2RA, ATG16L1, and PTPN2, as well as many genes not previously associated with inflammatory bowel disease. More than half of the prioritized genes had not been linked previously to inflammatory bowel disease in curated datasets.
Among the unexpected findings was CLN3, a gene previously associated with Batten disease. Functional studies in a mouse ILC3-like cell line showed that increased Cln3 expression altered inflammatory gene expression and reduced secretion of IL-17, IL-22, and granulocyte-macrophage colony-stimulating factor during immune stimulation, suggesting a previously unrecognized role for the gene in regulating ILC3 function.
The researchers also applied their approach to asthma, celiac disease, ulcerative colitis, inflammatory bowel disease, and primary sclerosing cholangitis. Across these conditions, prioritized genes were enriched in pathways involved in cytokine signaling and ILC3 activation, supporting a broader role for these cells in immune-mediated disease.
Although the findings are preclinical, the study provides a reference map that could help laboratories and researchers assign biological function to noncoding disease-associated variants identified through genomic testing. By linking genetic risk loci to their likely target genes in a clinically relevant immune cell type, the resource may support future efforts to improve interpretation of genomic data and identify candidates for functional validation.
Newsletters
Receive the latest pathologist news, personalities, education, and career development – weekly to your inbox.
